Synthesis of biologically active natural products, aspergillides A and B, entirely from biomass derived platform chemicals

Article abstract of DOI:10.1039/c5gc00900f

The depletion of finite fossil fuels drives the need to develop sustainable chemical feedstock such as biomass. The synthesis of biologically active natural products aspergillides A and B was achieved whereby all the carbon atoms present originated from biomass derived platform chemicals such as ethanol, levulinic acid and 5-hydroxymethylfurfural (HMF). The key steps in this synthesis include Noyori's asymmetric transfer hydrogenation, Achmatowicz rearrangement coupled with a triple reduction sequence, micellar Negishi coupling as well as an enzymatic kinetic resolution. Lipshutz's micellar Negishi coupling was also successfully applied on an advanced synthetic intermediate for the first time with good yield and excellent selectivity. This synthesis demonstrates the feasibility of constructing biologically active compounds using a sustainable chemical feedstock like biomass.

Full text of DOI:10.1039/c5gc00900f

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Synthesis of biologically active natural products,
aspergillides A and B, entirely from biomass
derived platform chemicals†
Cite this: DOI: 10.1039/c5gc00900f
Received 28th April 2015,
Accepted 18th May 2015
a
a,b,c
DOI: 10.1039/c5gc00900f
P.-F. Koh and T.-P. Loh*
www.rsc.org/greenchem
The depletion of finite fossil fuels drives the need to develop sus-
tainable chemical feedstock such as biomass. The synthesis of bio-
logically active natural products aspergillides A and B was achieved
whereby all the carbon atoms present originated from biomass
derived platform chemicals such as ethanol, levulinic acid and
5
-hydroxymethylfurfural (HMF). The key steps in this synthesis
include Noyori’s asymmetric transfer hydrogenation, Achmatowicz
rearrangement coupled with a triple reduction sequence, micellar
Negishi coupling as well as an enzymatic kinetic resolution. Lip- Fig. 1 Structures and biological activities of aspergillides A, B and C.
shutz’s micellar Negishi coupling was also successfully applied on
an advanced synthetic intermediate for the first time with good
yield and excellent selectivity. This synthesis demonstrates the
materials and this mindset has to be reconsidered in view of
sustainability and potential cost savings.
feasibility of constructing biologically active compounds using a
sustainable chemical feedstock like biomass.
Aspergillides A, B and C are secondary metabolites, isolated
from the marine fungus Aspergillus ostianus strain 01F313 by
Kusumi’s group in 2008, which exhibit potent cytotoxic activi-
Biomass holds great promise to be a sustainable surrogate
feedstock for both fuels and chemicals, in place of convention-
1
ties towards mouse lymphocytic leukemia cell (L1210) with
al fossil fuels, due to its renewability and abundance.
−
1
−1
−1
LD50 values of 2.1 μg mL , 71.0 μg mL and 2.0 μg mL
Biomass derived platform chemicals such as ethanol, levulinic
acid and 5-hydroxymethylfurfural (HMF) are highlighted to be
among the “top chemical opportunities from biorefinery
4
respectively (Fig. 1). A comprehensive review of prior syn-
theses of aspergillides A, B and C has been succinctly summar-
5
2
ized up to 2011 and several recent syntheses have also been
carbohydrates”. Bioethanol is produced industrially while
6
reported. Notably, Shishido’s synthesis in 2011 provided a
levulinic acid production from biomass has been commercia-
lized and a pilot plant has been set up for HMF production in
the form of HMF ether. In continuation of our group’s efforts
stereodivergent strategy to access both aspergillides A and B,
7
and that the former could be isomerized to the latter.
3
We envisaged that aspergillide A, and hence aspergillide B,
could be synthesized entirely from biomass derived platform
chemicals, except for the protecting groups and reagents used,
with the following disconnections (Fig. 2). The macrocycle can
in biomass conversion, we envisaged the synthesis of biologi-
cally active natural products entirely from biomass derived
platform chemicals as synthesis in chemistry has traditionally
employed chemicals derived from fossil fuels as starting
8
be constructed using Yamaguchi macrolactonization, while
9
Negishi coupling connects fragments A and B where fragment
A can be derived from levulinic acid 4 and fragment B can be
derived from HMF 5 and ethanol through a series of
transformations.
Our synthesis began with the construction of enantio-
enriched fragment A from levulinic acid 4 (Scheme 1). 4 was
a
Division of Chemistry & Biological Chemistry, Nanyang Technological University,
5
b
0 Nanyang Avenue, Singapore 639798. E-mail: teckpeng@ntu.edu.sg
Hefei National Laboratory for Physical Sciences at the Microscale and Department
of Chemistry, University of Science and Technology of China, Hefei, 230026,
P. R. China
completely reduced by using LiAlH to afford racemic diol 6 in
4
c
Collaborative Innovation Center of Chemistry for Energy Materials, P. R. China
8
8% yield. Subsequently, 6 was subjected to an enzymatic
†
Electronic supplementary information (ESI) available: Characterization data for
1
0
kinetic resolution whereby the primary alcohol is acetylated
first followed by enantioselective acetylation of one enantiomer
all new compounds, experimental procedures. CCDC 1047243. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/c5gc00900f
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Scheme 2 Synthesis of enantioenriched fragment B from HMF 5.
Fig. 2 Constructing aspergillide
A from biomass derived platform
chemicals.
Scheme 3 Achmatowicz rearrangement and triple reduction sequence
to access intermediates 17 and 18 with the desired stereochemistry.
With the enantioenriched β-hydroxyester 13 in hand, we
1
1,17,18
proceeded with the Achmatowicz rearrangement
mCPBA to give the hemiacetal 15 in a diastereomeric ratio of
1 : 9 where the major isomer is presumed to be the one where
Scheme 1 Synthesis of enantioenriched fragment A from levulinic the hydroxyl group is in the axial position due to the anomeric
using
9
1
9
acid 4.
effect (Scheme 3). The crude mixture of 15 could be reduced
to give 16 with 61% unoptimized yield over 2 steps. Further
1
1
optimization by temperature control and excess reagents
1
1
of the secondary alcohol. After several optimizations, the allowed us to access the THP core of aspergillide A with the
crude mixture of 7 and 8 could be directly protected as a silyl desired stereochemistry20 by employing the Achmatowicz
ether 9 in 40% yield over 2 steps out of the theoretical rearrangement followed by a triple reduction sequence where
maximum of 50% and with excellent enantiomeric excess of the formation of the desired endo-alcohol is rationalized to be
>
99%. The acetate group in 9 was selectively removed using due to the steric hindrance of the axial α-hydrogen atoms on
K2CO3 to afford primary alcohol 10 in 96% yield and then the exo face. Pyrans 17 and 18 were synthesized with a com-
1
2
efficiently iodinated to afford enantioenriched fragment A 11 bined yield of 75% over steps from 13, where 17 is formed
in 98% yield.
from the initial hemiacetal reduction of 15 to 16 followed by
Next, we focused on the synthesis of enantioenriched frag- a 1,2-reduction while 18 is formed from a 1,4-reduction of 16
ment B from HMF 5 (Scheme 2) by subjecting 5 to a benzyla- followed by a 1,2-reduction.
1
3
tion reaction to afford 12 in 91% yield. At this stage, we
Both 17 and 18 could be protected as the TBS ether to yield
19 and 20 as an inseparable mixture (Scheme 4). Removal of
1
4
attempted several asymmetric Mukaiyama aldol reactions
1
1
but no satisfactory results were obtained.
decided to attempt dynamic enzymatic kinetic resolutions
on the racemic aldol product rac-13 but again no satisfactory yield. Swern oxidation of the primary alcohol 21 to aldehyde
results were obtained. Fortunately, by oxidizing rac-13 to 14 22 in 85% yield followed by Takai iodo-olefination
keto : enol form = 93 : 7) and performing an asymmetric trans- vinyliodide 23 as a separable mixture of E and Z isomers with
Instead, we the benzyl protecting group in 19 and 20 as well as hydrogen-
1
5
ation of the double bond provided a single product 21 in 96%
2
1
1
1
11,22
gave
(
1
6
fer hydrogenation, enantioenriched β-hydroxyester 13 was a combined yield of 82%. The relative stereochemistry of the
synthesized in 99% yield with an excellent enantiomeric excess THP core was confirmed using single crystal X-ray crystallo-
2
3
of 98%.
graphy analysis (Fig. 3).
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Scheme 6 Completion of the synthesis of aspergillides A and B.
Scheme 4 Completing the synthesis of enantioenriched fragment B.
Negishi coupling on an advanced intermediate in total syn-
thesis. At this stage, the TBS group was deprotected using
TBAF to give 25 and reprotected as MOM ether to give 26 in
83% yield over 2 steps. 26 was subsequently hydrolyzed under
basic conditions to yield the seco acid 27. As the macrolactoni-
zation of seco acid 27 followed by deprotection to afford
8
d
aspergillide A 1 has been reported and the isomerization
of aspergillide A 1 to aspergillide B 2 has been reported by
7
Shishido’s group, this completes the formal syntheses of
aspergillides A and B (Scheme 6).
Conclusions
The synthesis of biologically active natural products aspergil-
lides A and B was achieved with biomass derived platform
chemicals. All the carbon atoms present in aspergillides A and
B are derived entirely from biomass platform chemicals such
as levulinic acid, HMF and ethanol. The key steps in this syn-
thesis include Noyori’s asymmetric transfer hydrogenation,
Achmatowicz rearrangement coupled with a triple reduction
sequence, the first application of Lipshutz’s micellar Negishi
coupling as well as an enzymatic kinetic resolution. This chal-
lenges the current perceptions of synthesis with fossil fuels’
derived chemicals and serves as a precedent for the use of
biomass platform chemicals in the synthesis of complex bio-
logically active natural products.
Fig. 3 ORTEP drawing of rac-23.
Acknowledgements
This research was supported financially by the National
Natural Science Foundation of China (21372210), the Nanyang
Technological University, the Singapore Ministry of Education
Academic Research Fund (MOE2014-T1-001-102, MOE2012-T1-
Scheme 5 Micellar Negishi coupling and synthesis of seco acid 27.
001-107) and the National Environment Agency (NEA-ETRP
Project Ref. No. 1002 111). The authors would like to thank
Dr Ganguly (NTU) and Dr Li (NTU) for their assistance with
single-crystal X-ray crystallography.
With the completion of both fragments A and B, we set out
to attempt the Negishi coupling reaction by adopting the use
of designer surfactants reported by Lipshutz’s group in recent
9
c,24
years.
This variant of the Negishi coupling offers a variety
of advantages such as the use of water as the reaction solvent
and avoiding the prior preparation of an organozinc coupling
partner. After several rounds of optimization, we were
Notes and references
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(Scheme 5). This represents the first application of micellar
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